The goal of SPORE Project 1 is to develop effective strategies for early detection of ovarian cancer in women at average risk for the disease. The possibility of screening is based on several biological assumptions: 1) that ovarian cancers generally arise from clones of cells;2) that most metastatic disease arises from clinically detectable lesions isolated to the ovary;and 3) that there is a reasonable interval from the development of invasive cancer to conventional diagnosis of the disease. Over the years, SPORE investigators have addressed each of these questions demonstrating that most ovarian cancers are clonal and that there may be as much as 1.9 years from the initial growth of an ovarian cancer prior to its clinical detection. During the project period we have found that alterations in gene expression in early stage high grade serous cancers resemble those in late stage disease, consistent with the development of stage III/IV from stage I lesions. Given the prevalence of ovarian cancer among postmenopausal women, a diagnostic strategy must be moderately sensitive (>75%), but highly specific (>99.6%) to achieve a positive predictive value of 10%, i.e., 10 laparotomies for each case of ovarian cancer detected. One of the most promising approaches to early detection of this neoplasm is to use rising values of a serum marker such as CA 125 to prompt the performance of transvaginal sonography (TVS). Patients with abnormal TVS or a sufficiently rapid rise in CA 125 undergo exploratory surgery. If one is to pursue a two-stage strategy for early detection, the initial stage must be optimally sensitive. No single marker is likely to be adequately sensitive and multiple markers may be required to detect the full spectrum of ovarian cancers. Simple addition of multiple markers may increase sensitivity, but generally decreases specificity, posing a particular problem in a disease with the prevalence of ovarian cancer. Consequently, the Specific Aims of this grant are: 1) to identify an optimally sensitive panel of known and novel markers for ovarian cancer that, in aggregate, detect >90% of early stage cancer;2) to develop and test statistical techniques which permit utilization of multiple markers over time to detect early ovarian cancer, increasing sensitivity without compromising specificity;and 3) to conduct a screening trial in women at average risk to determine whether the CA 125 algorithm achieves a positive predictive value of 10% and to build a bank of serum and plasma specimens from the same volunteers over a period of years. During the last 41/2 years we have identified candidate tumor markers using proteomic, genomic and lipomic techniques, found markers that complement CA 125, developed Luminex assays for selected markers, established a novel system to study the impact of individual oncogenes and tumor suppressor genes on ovarian oncogenesis, developed mathematical techniques to use markers in combination, and initiated a clinical screening trial with a consortium of collaborating institutions. Continued support of this project will permit identification and validation of a panel of biomarkers, development of statistical techniques that permit utilization of multiple biomarkers overtime, and completion of a screening trial using the CA 125 algorithm.